Camptothecin derivatives are DNA-topoisomerase I inhibitors that have emerged as a prominent class of anticancer agents. Together with the taxanes, the topoisomerase I inhibitors are presumably the most important new class of anticancer drugs introduced into clinical practice. Pre-clinical studies demonstrated significant in vitro and in vivo activity of topoisomerase I inhibitors, such as camptothecin and its derivatives, on a broad range of tumors. The results from clinical trials were promising, as shown by the registration of two topoisomerase inhibitors, topotecan and irinotecan (also known as CPT-11), in many European countries and in the USA, for treatment of patients with ovarian and colorectal cancer, respectively. Other derivatives are currently at different stages of clinical development.
In patent application EP1044977 and in J. Med. Chem. 2001, 44, 3264-3274, camptothecin derivatives are described which bear an alkyloxime O-substituted at position 7 and which are endowed with antitumor activity higher than the compound of reference topotecan. Moreover these camptothecin derivatives bearing an imino group on position 7, also show an improved therapeutic index. Among these compounds one of the preferred molecules was shown to be 7-t-butoxyiminomethylcamptothecin (CPT 184, also known as ST1481 or gimatecan).
The main property of camptothecin analogues is their activity against DNA topoisomerase I, but beyond this similarity the compounds differ widely in terms of antitumor activity, pharmacology and metabolism. Despite the good tolerability and efficacy of camptothecins in animal models, their low therapeutic index still remains a major drawback for their clinical use, together with the reversibility of the drug interaction in the ternary complex (drug-enzyme-DNA) and the instability of the lactone ring, which preclude their efficacy against slowly-growing tumors. Lastly, experimental models showed that camptothecins anti-tumor activity is strongly dependent upon the drug administration schedule, in fact require either a prolonged schedule of administration at low doses, or frequent intermittent dosing schedules.
Although new cancer drugs have been developed and consequently some malignancies are now curable, drug resistance to chemotherapies, including camptothecin derivatives, is a major limitation to therapy in several human tumours and there are still numerous primary and recurrent, refractory cases. DNA topoisomerase I has recently been investigated to define the mechanism in naïve or acquired resistance to Topotecan or CPT-11 and several mutations that impact on resistance to camptothecin derivatives have been identified in several regions of human topoisomerase I (Benedetti et al. 1993. Cancer Res 53. 4343; Fiorani et al. J Biol. Chem. 2003; Oct. 31; 278 (44):43268-75; Chrencik et al. 2004; JMB 339, 773-784).
Furthermore mutations in topoisomerase I occurred after chemotherapy with CPT-11 in NSCLC patients suggested that the development of resistance to irinotecan in some patients may involve topoisomerase I mutation (Tsurutani et al. 2002 Lung cancer 35. 299-304).
Although the significance of topoisomerase I mutations to CPT resistance needs to be further investigated, it is considered of great clinical interest to have a camptothecin derivative that, besides its typical pharmacological profile, shows an activity on mutated topoisomerase I.